(1) Food-schedule intermittency can induce several sorts of chronic, excessive behaviors, including oral drug overindulgence. Under these schedule-induction conditions, animals will be allowed a concurrent choice to work for either a drug solution (cocaine, caffeine or nicotine) or water to investigate how both pharmacological and nonpharmacological factors come to contribute to the selection and maintenance of substance abuse. (2) The conditions under which selective acquisition of oral drug abuse occurs (intermittency of a crucial reinforcer, facilitation by conditioned reinforcers) may model the crucial participation of nonpharmacological factors operative when humans acquire substance abuse (lack of rewarding alternatives, facilitation by social reinforcers). The parameters of abuse induction will undergo analysis. (3) Gateway agents affecting acquisition, and agonist and antagonist drugs affecting the drug abuse, will be assessed. (4) The behavioral consequences of cocaine, caffeine and nicotine, both when injected and when taken by oral overindulgence will be measured by a variety of behavioral techniques (e.g., locomotor activities, fine-motor task performance, timing capacities) and (5) related quantitatively in parallel studies to serum drug and metabolite pharmacokinetics. (6) The effects of simultaneous exposure to two-drug combinations will evaluate possible synergistic or ameliorative outcomes, particularly when a licit agent is taken along with cocaine. (7) The simultaneous coabuse of ethanol and cocaine is frequent for cocaine abusers, and the possible contributary action of the active metabolite cocaethylene will be evaluated behaviorally. (8) The effect of both chronic schedule-induced vehicle and cocaine drinking on brain regional monoamines and their metabolites will be investigated. (9) A pharmacologic analysis of caffeine's action will be tried using adenosine agonist and antagonist agents with 1 or 2 behavioral techniques.
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